B63 Tumors and tumor like lesions of the liver

Question 1

Tumor-like lesions

Answer 1

1. Focal nodular hyperplasia
   
   • Formed due to local vascular injury of that region
   • Hyperplastic hepatocytes nodules around a pericentral fibrous scar.
   • Found in non-cirrhotic livers
2. Macroregenreative nodules
   
   • Found in cirrhotic livers
   • Nodules of hyperplastic hepatocytes that do not show atypia or dysplasia
   • Cotain more than one portal tract
3. Dysplastic Nodules
   
   • Nodules of highly proliferative, dysplastic cells in a cirrhotic liver
   • Cell crowding, polymorphism, and atypia
   • Degree of dysplasia decides whether it is low- or high-grade
   • These are precursor lesions to hepatocellular carcinoma.
   • The nodules may be monoclonal.

Question 2

What are the benign tumors of the liver?

Answer 2

Hepatic Cavernous Hemangiomas - just like cavernous hemangioma elsewhere.

• well circumscribed, endothelial lined vascular channels and stroma
• red/blue soft nodules, usually directly under the capsule.
• main risk is to actually mistake them for solid lesions and take a biopsy, which can cause severe intra-abdominal bleeding.

Von Meyenbrug hamartomas

• hamartomas of disorganized bile duct tissue surrounded by dense collagenous stroma
• totally benign

Hepatic adenomas

• more info on its card

Granulomatous disease

• infectious, fungal, TB
• sarcoidosis
• primary biliary cirrhosis
• parasitic infections
• incidental/idiopathic - not clinically impactful

Question 3

Describe hepatic adenoma

Answer 3

• Occurs in women using oral contraceptives, and men using anabolic steroids.
• Well demarcated, but non-capsulated
• Can be very large, up to 30cm
• Pale yellow/tan or bile stained, solid tumors.
• Forms sheets/cords of normal looking hepatocytes, but lacking the normal lobular pattern, and arteries and veins are distributed throughout, and there are no portal vessels.
• May be mistaken for hepatocellular carcinoma
• Subcapsular adenomas can cause capsule rupture and lethal abdominal bleeding.
• Have a low potential risk of transforming to hepatocellular carcinoma

Three discrete classifications of adenomas:

1. With Biallelic inactivation of HNF1A or CYP1B1
   
   • ​​very low risk of transformation
   • more common in women on oral contraceptives
2. With Activating mutations to beta-catenin
   
   • high risk for malignant transformation
   • more common in men with anabolic steroids or NAFLD
3. Inflammatory adeonmas
   
   • associated with increased SAA adn CRP levels in the tumor and serum

Question 4

What are the main pre-cancerous lesions of the liver, histologically

Answer 4

Adenomas - especially those with activating beta catenin mutaitons, however these are the least frequent sources of HCC.

Small cell change - very small hepatocytes with normal-sized and hyperchromatic nuclei. These are dysplastic cells that are directly pre-malignant.

Dysplastic nodules - dysplastic nodules indicate areas of high mutation, out of which cancerous cells can arise, these usually occur in a cirrhotic liver and are the most common source of hcc.

Question 5

What are the most common malignant tumors of the liver?

Answer 5

Metastatic cancers. From:

• Colon
• Lung
• Breast

Primary malignant tumors of the liver are still very common, but less than the metastatic ones.

Question 6

What are the primary malignant tumors of the liver?

Answer 6

Virtually all are Hepatocellular carcinomas

Question 7

Epidemiology of hepatocellular carcinoma

Answer 7

Most prevalent in countries with endemic hepatitis B infection, South Asia and Sub-saharan Africa.

Also associated with high aflatoxin exposure

In endemic regions, peak incidence is at 20-40 years old and in 50% of cases appears prior to cirrhosis.

The HBV genome contains a gene known as HBx, and hepatocellular cancers develop in mice transgenic for this gene. HBx can directly or indirectly activate
a variety of transcription factors and several signal transduction pathways.

In the US and europe, it is most associated with Hepatitis C infections, and rarely appears before age 60, and 90% of the cases occur after cirrhosis.

In all cases, there is strong male predominance, 3:1 in the US and europe and 8:1 in endemic regions.

Whatever the source, it typically arises from high-grade dysplastic nodules with small cell change.

Other sources:

• All of the sources of cirrhosis
• Acohol, nonalcoholic liver disease
• hemochromatosis, a1-antitrypsin deficiency
• the rare disorder hereditary tyrosinemia - 40% develop hcc.

In rare cases, Fibrolamellar Hcc occurs in young adults of both sexes with no association of any other risk factors.

Question 8

What is an important mutation even in developing hepatocellular carcinoma? What are other major genetic associations?

What is the serologic tumor marker?

Answer 8

Activation of the nuclear factor-κB (NF-κB) pathway. Activation of the NF-κB pathway within hepatocytes blocks apoptosis

There are always major structural and numeric chromosomal changes (aneuploidy) indicating large scale genomic instabilty.

Alpha fetoprotein.

Question 9

What cells does HCC arise from

Answer 9

Mature hepatocytes and/or progenitor cells called ductular cells/oval cells.

Question 10

Gross morphology of hcc.

Answer 10

A single primary hcc can take on multiple morphologies

1. Unifocal, very large tumor
2. Multifocal nodules
3. Diffusely infiltrative without distinct nodules.

Tumors are yellow/white, with areas of bile stainig, hemorrhage, and necrosis

Hcc has a strong tendency for vascular invasion and growth into the lumen and walls of the portal vein, inferior vena cava, and even extending into the right heart.

Question 11

Histology of HCC

Answer 11

Can be well differentiated cells forming cords or glandular patterns, often with bile globules and pseudocanaliculi.

or

Poorly differentiated cells with large, anaplastic cells, with multinucleated giant cells.

In either case it is a cellular tumor with very little stroma.

In the unusual fibrolamellar form, it is a single tumor of these cells , but importantly has prominent fibrous bands running through it.

Question 12

Clinical features of hcc,

how does it present, what is the prognosis, causes of mortality, and treatment

Answer 12

Since it usually arises on the backround of cirrhosis

• Sudden rapid hepatomegaly
• Sudden worsening of ascites
• Appearance of blood in the ascites
• Development of fever and pain

Alpha fetoprotein expression is seen in the serum, but not until the tumor is well advanced, and only in about 50% of cases, and also can give false positives due simply to liver necrosis and cirrhosis.

The better screening method is Radiologic screening every 6 months for patients with known cirrhosis.

Without treatment median survival is 7 months, mortality caused by:

• Extreme cachexia
• Variceal bleeding
• Liver failure and hepatoencephalopathy induced coma
• Tumor rupture and fatal hemorrhage

Resection can be temproarily helpful, but there is high frequency of new de novo tumor formation in the diseased liver.

Liver transplant can be curative.